Respiratory Epithelial Cells: More Than Just a Physical Barrier to Fungal Infections

Abstract

The respiratory epithelium is highly complex, and its composition varies along the conducting airways and alveoli. In addition to their primary function in maintaining the respiratory barrier and lung homeostasis for gas exchange, epithelial cells interact with inhaled pathogens, which can manipulate cell signaling pathways, promoting adhesion to these cells or hosting tissue invasion. Moreover, pathogens (or their products) can induce the secretion of chemokines and cytokines by epithelial cells, and in this way, these host cells communicate with the immune system, modulating host defenses and inflammatory outcomes. This review will focus on the response of respiratory epithelial cells to two human fungal pathogens that cause systemic mycoses: Aspergillus and Paracoccidioides. Some of the host epithelial cell receptors and signaling pathways, in addition to fungal adhesins or other molecules that are responsible for fungal adhesion, invasion, or induction of cytokine secretion will be addressed in this review.

Keywords: Aspergillus; Paracoccidioides; adhesion; airway; cytokine; epithelial cell; invasion; lung; respiratory.

Figure 1

Examples of the responses of respiratory epithelial cells to Aspergillus infection. (a) Aspergillus conidia can bind to extracellular matrix (ECM) proteins and epithelial cell surface. Conidia may germinate on the surface of epithelial cells, and the resulting hyphae can actively invade the cells. Conidia internalization may occur through fungal CalA interaction with host α5β1 integrin and WIPF2, Arp2/3, and actin reorganization. Conidia can also be trafficked in the endosomal system and germinate in phagolysosomes, reentering the extracellular space. (b) Cytokine secretion by epithelial cells may be a result of (i) the interaction of Aspergillus hyphae with TLR2, activating MyD88; (ii) the activation of PI3K and MAPKs by germinating conidia; (iii) the opsonization of Aspergillus conidia by ficolins and MAPK activation; (iv) interaction with dectin-1 and the activation of NF-κB; and (v) activation of MAPKs and the transcription factor AP-1 by Aspergillus proteases. Aspergillus proteases can also activate PAR2, inducing cytokine production. Created with Biorender.com.

Figure 2

Responses of respiratory epithelial cells to Paracoccidioides infection. (a) Paracoccidioides yeasts can bind to host ECM proteins and α3 and α5 integrins. Fungal adhesion is also dependent on lipid raft clustering, which promotes Src-family kinase (SFK) and ERK1/2 activation. (b) Paracoccidioides induces IL-8 cytokine secretion in epithelial cells by interacting with α3 and α5 integrins and TLR2. Fungal proteases may also activate PAR-1 and PAR-2 in epithelial cells, leading to IL-8 production. The secretion of IL-8 is promoted by Paracoccidioides and is dependent on lipid raft clustering and the activation of MAPK (p38MAPK, ERK1/2) and PKCδ. Created with Biorender.com.